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J. Biol. Chem., Vol. 282, Issue 41, 30014-30021, October 12, 2007

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Skeletal Muscle Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1 Muscle-specific Knock-out Animals^*

Christoph Handschin¹, Sherry Chin, Ping Li^¶, Fenfen Liu^||, Eleftheria Maratos-Flier^||, Nathan K. LeBrasseur^**, Zhen Yan^¶, and Bruce M. Spiegelman²

From the Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland, ^¶Department of Medicine, Duke University Medical Center, Durham, North Carolina 27704, ^||Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and ^**Diabetes and Metabolism Unit, Boston University School of Medicine, Boston, Massachusetts 02118

The transcriptional coactivator peroxisome proliferator-activated receptor coactivator 1 (PGC-1) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1 in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Whole body PGC-1 knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1 knock-out mice to identify a specific role for PGC-1 in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1 knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1 in maintenance of normal fiber type composition and of muscle fiber integrity following exertion.

Received for publication, June 12, 2007 , and in revised form, July 5, 2007.

^* This work was supported in part by National Institutes of Health Grants DK54477 and DK61562 (to B. M. S.) and AR050429 (to Z. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Supported by a Scientist Career Development grant from the Muscular Dystrophy Association, Swiss National Science Foundation Professorship PP00A-110746, and the University Research Priority Program "Integrative Human Physiology" of the University of Zurich.

² To whom correspondence should be addressed: Dana-Farber Cancer Institute, Smith Bldg., One Jimmy Fund Way, Boston, MA 02115. Tel.: 617-632-3567; Fax: 617-632-4655; E-mail: bruce_spiegelman{at}dfci.harvard.edu.

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